EP0804245A1 - Preparation de collagene pour la liberation controlee de principes actifs - Google Patents

Preparation de collagene pour la liberation controlee de principes actifs

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Publication number
EP0804245A1
EP0804245A1 EP95916664A EP95916664A EP0804245A1 EP 0804245 A1 EP0804245 A1 EP 0804245A1 EP 95916664 A EP95916664 A EP 95916664A EP 95916664 A EP95916664 A EP 95916664A EP 0804245 A1 EP0804245 A1 EP 0804245A1
Authority
EP
European Patent Office
Prior art keywords
collagen
collagen preparation
preparation according
active ingredient
release
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP95916664A
Other languages
German (de)
English (en)
Other versions
EP0804245B1 (fr
Inventor
Michael Roreger
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
LTS Lohmann Therapie Systeme AG
Lohmann and Rauscher GmbH and Co KG
Original Assignee
LTS Lohmann Therapie Systeme AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by LTS Lohmann Therapie Systeme AG filed Critical LTS Lohmann Therapie Systeme AG
Priority to SI9530289T priority Critical patent/SI0804245T1/xx
Publication of EP0804245A1 publication Critical patent/EP0804245A1/fr
Application granted granted Critical
Publication of EP0804245B1 publication Critical patent/EP0804245B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/24—Collagen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/32—Proteins, polypeptides; Degradation products or derivatives thereof, e.g. albumin, collagen, fibrin, gelatin
    • A61L15/325—Collagen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00005—The prosthesis being constructed from a particular material
    • A61F2310/00365—Proteins; Polypeptides; Degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/80—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special chemical form
    • A61L2300/802—Additives, excipients, e.g. cyclodextrins, fatty acids, surfactants

Definitions

  • a number of polymers are used, which should impart the desired properties to the respective dosage form depending on the place of use.
  • Wound treatment agents and implantable materials should be adapted to the surface of the respective application site and body cells such as Do not interfere with keratinocytes, fibroblasts or endothelial cells in their function and activity.
  • the range of polymers that can be used is therefore limited to those which have excellent compatibility when in contact with connective tissue and are preferably biodegradable.
  • Solutions of telopeptide-free, acid-soluble collagen are generally used to produce collagen matrices, as described, for example, in US Pat. No. 5,024,841, US Pat. No. 4,789,663, US Pat. No. 4,774,091, US Pat. No. 4,563,350, US Pat. No. 5,246,457 or EP 429,438 used, from which reconstituted fibrils are obtained by means of dialysis, pH shifts or other methods, which are then preferably processed into porous matrices by means of different methods.
  • these preparations can have excellent biocompatibility since they consist of pure collagen, they have the disadvantage that, due to the use of soluble collagen, they only delay the release of the active substance to a limited extent.
  • Such a delay in release can be achieved by reducing the solubility of the collagen matrix by using crosslinking or binding agents such as e.g. in US 4 409 332, DE 2 843 963, WO 93/00890 or WO 85/04413, by using lacquering agents, as described in DE 38 41 397, or by combining water-soluble collagen with other polymers, preferably natural anionic polymers or their derivatives.
  • crosslinking or binding agents such as e.g. in US 4 409 332, DE 2 843 963, WO 93/00890 or WO 85/04413, by using lacquering agents, as described in DE 38 41 397, or by combining water-soluble collagen with other polymers, preferably natural anionic polymers or their derivatives.
  • laminates are produced from water-soluble and / or water-insoluble collagen, which consist of one or more active substance-containing reservoir layers and a layer which delays the active substance release.
  • such laminates could allow a delay in release while minimizing the toxicological risks, but they have the disadvantage that they are extremely expensive to produce and that the layers only adhere to one another with "moist" films become can. Dry films, such as are absolutely necessary for active substances susceptible to decomposition, cannot, for example, be combined to form such laminates.
  • EP 224 453 therefore describes a collagen matrix which mainly consists of water-insoluble, reticulated collagen and additionally contains water-soluble, non-reticulated collagen.
  • this soluble collagen acts as an active substance, which is released after application by natural skin moisture or by extreme moistening of the preparation and has an effect on the skin.
  • Active ingredients can be incorporated into the preparation for pharmaceutical purposes, which after application together with the soluble collagen are then very quickly removed from the collagen matrix and released.
  • Such a collagen preparation can be useful when rapid release is desired and sensible.
  • the collagen preparation contains different active ingredients. It can also contain auxiliaries such as viscosity regulators, binders, humectants, plasticizers, penetration accelerators, preservatives, disinfectants, pH regulators, antioxidants, active substance stabilizers, oils, fats, waxes, emulsion stabilizers, fragrances, dyes and / or inert fillers.
  • auxiliaries such as viscosity regulators, binders, humectants, plasticizers, penetration accelerators, preservatives, disinfectants, pH regulators, antioxidants, active substance stabilizers, oils, fats, waxes, emulsion stabilizers, fragrances, dyes and / or inert fillers.
  • the insoluble collagen is telopeptide-free, native, uncrosslinked type 1 collagen. It can be an insoluble collagen, which is a product obtained from calf skin by alkaline digestion.
  • the collagen preparation can be present in the form of powders, powders, microparticles, fibers, flakes, foams, sponges, needles, rods, tablets, gels, creams, single-layer films or laminates.
  • the collagen preparation can advantageously comprise combinations of different pharmaceutical forms.
  • the collagen preparation is preferably bioadhesive.
  • a method for producing the collagen preparation can include spray drying, freeze drying, coating or pouring with subsequent drying, phase separation and coacervation methods, compression or filling into containers.
  • the active ingredient release can also be influenced and / or controlled by the mixing ratio of acid-insoluble collagens with different molecular weight distributions. Furthermore, the active substance release can be controlled according to the method by dissolving or swelling or eroding the collagen preparation. A further possibility for controlling the release of active substance is possible by biodegrading the collagen preparation.
  • the use of the collagen preparation according to the invention consists in the controlled delivery of active ingredient to wounds.
  • the use can also be directed to the controlled delivery of active ingredient to intact skin.
  • the use of the collagen preparation can be used to implant or inject active substance into a living organism.
  • State-of-the-art collagen preparations for drug delivery are generally produced from acid-soluble collagen, that is to say collagen which is clearly dissolved in dilute acids at pH 2.
  • This acid-soluble collagen can be isolated from a range of tissues of animal and vegetable origin using a wide variety of methods.
  • the collagen used according to the invention is acid-insoluble collagen which, if it is present in an aqueous dispersion, cannot be dissolved even by adding concentrated acetic acid.
  • This insoluble collagen is preferably native collagen, which is predominantly present as type I collagen and to a lesser extent as type III collagen.
  • native collagen refers to a collagen molecule that has an unchanged triple-helical tertiary structure.
  • the insoluble collagen used according to the invention can be obtained by modification of processes such as those described, for example, in DE-OS 3034273, US Pat. No. 4,021,522 or DE-OS 27 16 602, by alkaline disruption from biomaterial of various origins.
  • Preferably 6 month old calf skin is used as the starting material.
  • a starting material of defined, constant quality is available, which in turn ensures the reliable reproducibility of those described below and in the Example 1 detailed process steps guaranteed.
  • the calf skin is first mechanically dehaired and degreased. Then soluble collagens and non-collagens soluble components of the connective tissue are extracted and discarded.
  • the connective tissue is first treated with an aqueous solution of an alkali metal hydroxide, preferably sodium hydroxide, and an alkali metal sulfate, preferably sodium sulfate, and then with an aqueous alkali metal sulfate solution for saponifying and removing the skin oils and for controlled swelling of the collagen fibers.
  • an alkali metal hydroxide preferably sodium hydroxide
  • an alkali metal sulfate preferably sodium sulfate
  • an aqueous alkali metal sulfate solution for saponifying and removing the skin oils and for controlled swelling of the collagen fibers.
  • a defined part of the intermolecular collagen bonds in the fiber composite of the swollen connective tissue is split by the treatment with alkali hydroxide / alkali sulfate or pure alkali sulfate solution depending on the concentration and the exposure time of the solutions.
  • the intramolecular bonds of the collagen are not attacked, so the helical structure of the molecule remains intact.
  • the connective tissue thus digested is washed out in several stages with water and dilute acids, cleaned and neutralized, then mechanically comminuted and dispersed in water.
  • the decisive step for the isolation of the acid-insoluble collagen with different molecular weight distributions used according to the invention is the targeted alkaline cleavage of the inter-molecular collagen bonds. If, for example, an aqueous solution of 9.75% sodium hydroxide and 9.2 ° sodium sulfate is allowed to act on the swollen connective tissue for 48 hours, the insoluble collagen in HPLC analysis (Biosil TSK-400 + column system) shows after dispersing in water Biosil TSK-125; eluent 0.5 m ammonium acetate buffer pH 6.7; detector UV 275 n, sensitivity range 0.02 AUFS) with evaluation against calibration protein chromatograms an average molecular weight of approx. 420,000.
  • HPLC analysis Biosil TSK-400 + column system
  • variable factors of the digestion process are the concentration and exposure time of sodium hydroxide.
  • concentration and exposure time of sodium hydroxide The higher the concentration of sodium hydroxide and / or the longer the exposure time of sodium hydroxide, the lower the average molecular weight of the isolated, acid-insoluble collagen, and vice versa.
  • one of the influencing factors that is to say concentration or exposure time, would have to be kept constant while the other was changed.
  • very short exposure times due to the higher sodium hydroxide concentration required as a result, lead to increased wear on production systems, such as, for example, line and filter systems, which cannot be implemented either because of the associated increase in operating costs.
  • the necessary sodium hydroxide exposure time and concentration must therefore be determined empirically for each problem individually so that they represent an optimum both with regard to the requirements for the pharmaceutical form and in particular with regard to the active ingredient release kinetics and from an economical point of view.
  • insoluble collagen has a significant influence on the properties of the collagen preparations produced therefrom by drying.
  • foams made from insoluble collagen of different molecular weight distributions produced by freeze drying show very different disintegration properties depending on the mixing ratio. While foams from 100% low-molecular, insoluble collagen in artificial wound secretion of pH 6.4 have completely disintegrated after 45 minutes, under the same conditions, foams from 100 ° C. higher molecular weight, insoluble collagen have not yet disintegrated even after 10 days.
  • the example shows that the use of high molecular weight collagen aggregates has a clearly stabilizing influence on the foam, which is expressed in significantly slower secretion uptake and swelling and in a very much delayed disintegration.
  • the shape stabilization by maintaining a high degree of natural cross-linking of the collagen has the decisive advantage, especially from a toxicological point of view, that additional manipulations to strengthen the structure, e.g. Tanning and crosslinking become superfluous.
  • the shape of the product is only stabilized by the fact that the original quaternary structure of the collagen, as it is present in the skin, is largely retained.
  • the collagen foams which were each made from only one basic type of insoluble collagen, therefore show clear differences, for example in relation to interaction with wound secretions.
  • such mono-preparations can only meet the requirement profile for a collagen product resulting from a specific application in special individual cases.
  • the present invention offers two things The possibility of tailoring the properties of a collagen preparation precisely to given product requirement profiles.
  • the molecular weight distribution of the insoluble collagen can be varied continuously in a very wide range by specifically controlling the cleavage of intermolecular bonds.
  • the required product properties can be adjusted by mixing these variations of insoluble collagen with different molecular weight distributions.
  • the active substances which are suitable for loading the collagen preparation are preferably active substances for dermal and transdermal application , Active substances for wound treatment and promotion of wound healing as well as active substances as are usually administered by means of preparations for implantation or injection.
  • active substances for dermal and transdermal application Active substances for wound treatment and promotion of wound healing as well as active substances as are usually administered by means of preparations for implantation or injection.
  • dermal treatment of local skin diseases local anesthetics, local antibiotics, antiseptics, antimycotics, antihistamines and antipruritic drugs, keratolytics and caustic drugs, antivirals, anti-rabies agents, steroids, as well as various substances for the treatment of acne, psoriasis or light dermatoses are used.
  • the active substances that are administered intradermally include, for example, steroidal and non-steroidal anti-inflammatory drugs, substances that promote blood circulation or vasoprotectors and constrictors for the treatment of vascular diseases.
  • the transdermally applicable active substances include, for example Neurolep- tika, antidepressants, tranquilizers, hypnotics, mulantien Psychosti-, analgesics, muscle relaxants, Antiparkinsonm.it- tel, ganglionic blockers, sympathomimetics, alpha-sympatholytic, beta-sympatholytic, antisympathotonics, antidiabetics, coronary, antihypertensives , Anti-asthmatics or diuretics.
  • the collagen preparation according to the invention can also be used on the skin in cosmetic preparations, for example in the form of foam masks or films for the treatment of, for example, aged skin, wrinkles or impure skin, for body care, for hair removal, for reducing perspiration or for light protection.
  • Active substances that are used in the collagen preparations according to the invention on external and internal wounds are preferably hemostatic active substances, among which collagen itself plays a special role, wound-cleaning active substances such as enzymes, antiseptics, disinfectants and antibiotics as well as active substances that promote wound healing, through which the Granulation stimulated, the formation of new vessels or the epithelization is promoted.
  • wound-cleaning active substances such as enzymes, antiseptics, disinfectants and antibiotics
  • active substances that promote wound healing through which the Granulation stimulated, the formation of new vessels or the epithelization is promoted.
  • biologically active peptides and proteins which develop high activities even in very low concentrations, and which are largely manufactured using recombinant technologies, are becoming increasingly important. tung.
  • These substances include so-called growth factors such as platelet derived growth factor (PDGF), epidermal growth factor (EGF), platelet derived endothelial cell growth factor (PD-ECGF), acidic Fibroblast growth factor (aFGF), basic Fibroblast growth factor (bFGF), Transforming growth factor ⁇ (TGF ⁇ ), Transforming growth factor ß (TGF ß), Keratinocyte growth factor (KGF), Insulin-like growth factors 1 and 2 ( IGF1, IGF2) and tumor necrosis factor (TNF).
  • growth factors such as platelet derived growth factor (PDGF), epidermal growth factor (EGF), platelet derived endothelial cell growth factor (PD-ECGF), acidic Fibroblast growth factor (aFGF), basic Fibroblast growth factor (bFGF), Transforming growth factor ⁇ (TGF ⁇ ), Transforming growth factor ß (TGF ß), Keratinocyte growth factor (KGF), Insulin-like growth factors 1 and 2 ( IGF1, IGF2) and tumor necrosis factor (TN
  • the active substances which are administered parenterally by means of the collagen preparation according to the invention include e.g. Antibiotics, antiseptics, anesthetics, analgesics of various strengths, cytostatics, hormones, steroids, cytokines such as e.g. Interleukins, interferons and colony stimulating factors, hormone releasing and release inhibiting factors, prostaglandins, enzymes and growth factors, in particular osteoinductive bone growth factors.
  • Collagen preparations according to the present invention offer the possibility of developing carrier systems with relatively few formulation basic building blocks, which are very flexible in their application and design options and which are very precisely tailored to the required problem solving can.
  • the mechanisms which give the release kinetics of the active substance its characteristic can be controlled in a targeted manner by mixing insoluble collagen of different molecular weights and shaping the collagen preparation. In addition to the structure and density of the polymeric collagen structure, these factors also influence the number and distribution of hydrophilic, hydrophobic and ionic binding sites along the polymer structure.
  • active substance can not only be enclosed in the cavities of a collagen preparation according to the invention, but can also be adsorbed onto the surface of the collagen structure, the bond strength between the collagen and active substance and thus also its release behavior is largely determined by ionic relationships and hydrophilic and hydrophobic interactions.
  • Another factor is added to collagen preparations for delivering active substance to external or internal wounds and to collagen preparations for implantation or injection.
  • the collagen preparations according to the invention come into contact with body fluid in the above-mentioned applications, the speed and extent of the liquid absorption by the collagen preparation and thus the swelling capacity and disintegration properties of the collagen preparation can be used as release control options, as shown in Example 2 already mentioned.
  • the breakdown of collagen preparation as a controlling mechanism
  • the removal of active ingredient from the collagen preparation by body fluid and the liquid-mediated diffusion of active ingredient from the core of the collagen preparation at its interface are particularly suitable.
  • the release is influenced by the biological degradation of the collagen preparation by means of hydrolysis and enzymatic action upon contact with body fluid.
  • auxiliaries can include additional polymers, e.g. serve as viscosity regulators when using liquid preparations or as binders in solid forms, e.g. Cellulose derivatives, starch derivatives, Galaktomannanderiva- te, dextrans, plant polysaccharides such as alginates, Pekti ⁇ ne, carrageenan, or xanthan, chitosan, proteins, Glykopro- proteins, proteoglycans, glucosaminoglycans, polyvinyl alcohol, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate Mischpolyme ⁇ risate, polyethylene glycol, polyacrylates and polymethacrylates, polylactides and polyglycolides as well as polyamino acids.
  • additional polymers e.g. serve as viscosity regulators when using liquid preparations or as binders in solid forms, e.g. Cellulose derivatives, starch derivative
  • the collagen preparation can comprise further auxiliaries
  • - Humectants such as glycerin, sorbitol, polyethylene glycol, polypropylene glycol
  • Plasticizers such as citric acid esters, tartaric acid esters or glycerol esters
  • Penetration accelerators such as, for example, alkyl sulfates, alkyl sulfonates, alkali soaps, fatty acid salts of polyvalent metals, betaines, amine oxides, fatty acid esters, mono-, di- or triglycerides, long chain alcohols, sulfoxides, nicotinic acid esters, salicylic acid, N-methylpyrrolidone, 2-pyrrolidone or urea.
  • Preservatives such as p-Cl-m-creole, phenylethyl alcohol, phenoxyethyl alcohol, chlorobutanol, methyl 4-hydroxybenzoate, propyl 4-hydroxybenzoate, benzalkonium chloride, cetyl pyridinium chloride, chlorhexidine diacetate or digluconate, ethanol or propylene glycol.
  • Disinfectants such as halogens such as polyvidone iodine, halogen compounds such as sodium hypochlorite or tosyl chloride sodium, oxidizing agents such as hydrogen peroxide or potassium permanganate, aryl mercury compounds such as phenyl mercuriborate or merbromin, alkyl mercury compounds such as thiomersal, organotinyl compounds such as tri-n-buti tin benzoate, silver-white compounds such as silver-white acetyltannate, alcohols such as ethanol, n-propanol or isopropanol, phenols such as thymol, o-phenylphenol, 2-benzyl-4-chlorophenol, hexachlorophene or hexylresorcinol or organic nitrogen compounds such as 8-hydroxyquinoline, chloroquinalol , Ethacridine, hexetidine, chlorhexidine or ambazon.
  • halogens such as
  • pH regulators such as, for example, glycine buffer, citrate buffer, borate buffer, phosphate buffer or citric acid-phosphate buffer.
  • Antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, tocopherol acetate, propyl gallate, butylated hydroxyanisole or butylated hydroxytoluene.
  • Active ingredient stabilizers such as mannitol, glucose, lactose, fructose, sucrose
  • Emulsifiable auxiliary substances such as oils, fats and waxes
  • Emulsion stabilizers such as non-ionic emulsifiers, amphoteric emulsifiers, cation-active emulsifiers and anion-active emulsifiers
  • microcrystalline cellulose aluminum oxide, zinc oxide, titanium dioxide, talc, silicon dioxide, magnesium silicate, magnesium aluminum silicate, kaolin, hydrophobic starch, calcium stearate or calcium phosphate.
  • Auxiliaries can e.g. be dissolved, dispersed or emulsified in dispersions of insoluble collagen before the drug formation process.
  • they can only be introduced in later stages of drug shaping in the manner known and customary for the respective shaping processes.
  • inventions of the collagen preparation according to the invention can be prepared using different methods known to those skilled in the art from mixtures of insoluble collagen dispersions, each with different molecular weights. Partitions are produced by, for example, spray drying, freeze drying, coating or casting with subsequent drying, phase separation and coacervation processes for particles or emulsified droplets, drying and compression, and simple filling into containers such as tubes and result in, for example, powders, powders, microparticles, fibers , Flakes, foams, sponges, needles, chopsticks, tablets, gels, creams, single-layer films or laminates. Preferred embodiments are spray-dried microparticles, freeze-dried foams and gel-like films produced by coating.
  • Active ingredient can be introduced into the collagen preparation according to the invention in such a way that active ingredient is dissolved or dispersed in the finished mixture of dispersions of insoluble collagen with different molecular weight distributions before the preparation molding process. If more than one active ingredient is to be incorporated, they can also be dissolved or dispersed separately from one another in the individual fractions of insoluble collagen before the mixing process. However, active ingredient can also be applied to or into the preparation after the preparation molding process has been carried out by coating, spraying, impregnation, immersion or other adsorption processes.
  • the collagen preparation according to the invention can contain, for example, a body fluid-soluble or at least swellable shell of insoluble collagen with a low average molecular weight in sponge or film form and a microparticulate preparation of insoluble collagen with a high dispersed therein include average molecular weight.
  • the outer sponge or film phase is used for the rapid release of active ingredient to quickly reach the minimum necessary active ingredient concentration, followed by a slower, more uniform release of active ingredient from the inner particulate phase to maintain the necessary active ingredient concentration over the application period.
  • Such release profiles can also be achieved with other preparation forms, such as fibers in hydrogels, sponge-like oil-in-water emulsions, compressed mixtures for implantable tablets, multilayer films, combinations of films and foams, etc.
  • Such multi-phase preparations can also be used if the release of different active ingredients at different times with different release rates is desired or if one or more active ingredients are to be released phasically, that is, at release-free intervals.
  • active ingredient A can be contained in a readily soluble, rapidly releasing outer phase, while active ingredient B is contained in a poorly soluble, retarded and controlled sustained releasing inner phase.
  • the outer and inner phases can release active substance, for example with the same kinetics.
  • the inner phase would be coated with an active substance-free layer of insoluble collagen which, after the outer phase has dissolved or has been exhausted, must first swell or dissolve in the active substance itself so that the active substance can be released from the inner phase. With this arrangement, an interval can be obtained in which no active ingredient is released.
  • flat embodiments such as films, membranes or thin sponges are preferred.
  • These two-dimensional designs can consist of laminates, which also include, for example, active substance-free barrier layers, permeable separating layers, control membranes and adhesive layers.
  • Substructures such as platelets, powders, microparticles or oil droplets can in turn be introduced into or between the individual layers in order to achieve the release kinetics suitable for one or more active ingredients.
  • Such single- or multi-layer collagen preparations are preferably provided for the applications mentioned, for example for protection against drying out or the ingrowth of germs, with a backing layer according to known methods and with a removable protective layer on the opposite side, the backing layer and protective layer being made of the materials familiar to the person skilled in the art, such as are used, for example, in the formulation of plasters or adhesive tapes.
  • the preparation form is porous, for example foam-like or sponge-like.
  • the size of the pores and the structure of the preparation is designed such that the immigration of cells such as fibroblasts or osteoblasts into the preparation is possible and the cells are given a structural orientation which is based in particular on the degree of order similar to that of natural connective tissue Collagen in the preparation according to the invention can be attributed.
  • the ingrowth of the cells may be necessary, for example, for the breakdown of the preparation or for the delivery or deposition of substances which are required, for example, for new tissue formation or for which Vascularization of a tissue which is to take the place of the collagen preparation according to the invention.
  • the collagen preparation according to the invention is admixed with additives such as e.g. Carboxymethyl cellulose, polyacrylic acid, tragacanth, sodium alginate or hydroxypropyl cellulose are adjusted to be bioadhesive, i.e. that it adheres to the surface tissue of the application site for a certain time by interfacial forces, so as to increase the dwell time at the application site or absorption site.
  • additives such as e.g. Carboxymethyl cellulose, polyacrylic acid, tragacanth, sodium alginate or hydroxypropyl cellulose are adjusted to be bioadhesive, i.e. that it adheres to the surface tissue of the application site for a certain time by interfacial forces, so as to increase the dwell time at the application site or absorption site.
  • the insoluble collagen After mechanical comminution and dispersion in H 2 O (pH 6.0), the insoluble collagen has an average molecular weight of approximately 2,500,000. The collagen concentration is 0.75 °.
  • the insoluble collagen After mechanical grinding and dispersion in H 2 0 (pH 6.0), the insoluble collagen has a medium 420,000.
  • the collagen concentration is 0.75 ° _.
  • Dispersion 1.1 Dispersion 1.2 A 100% 0%
  • each of the mixtures A to E were filled into deep-drawn parts with the dimensions 6 ⁇ 4 ⁇ 1.5 cm, shock-frozen and brought to a temperature of ⁇ 50 ° C. within 60 minutes. The mixtures were then freeze-dried.
  • the aging time was determined in 100 ml of the following buffer mixtures with gentle stirring:
  • pH 3 buffer mixture citric acid / sodium chloride / sodium hydroxide solution with addition of fungicide
  • pH 5 acetic acid (0.1 molar) sodium acetate (0.2 molar)
  • pH 6.4 artificial wound secretion (without albumin)
  • pH 7.5 Kaiium hydrogen phosphate / NaOH (0.1 molar / 0.1 molar)
  • the resulting lyophilisates (sponge weights approx. 250 mg, theoretical content lidocaine hydrochloride 10 mg) were each placed in a paddle apparatus and fixed to the bottom of the vessel with a net. 350 ml of water at a temperature of 37 ° C. were added to the apparatus and the mixture was stirred at 45 rpm. After 24 hours, samples of the release medium were taken. The active substance content was determined at 262.5 nm with a 1 cm layer thickness UV-photometrically with evaluation on the basis of a calibration curve.

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Abstract

Une préparation de collagène pour la libération contrôlée de principes actifs se caractérise en ce qu'elle comprend des mélanges de collagènes non solubles dans l'acide, ayant différentes répartitions de poids moléculaire.
EP95916664A 1994-04-27 1995-04-15 Preparation de collagene pour la liberation controlee de principes actifs Expired - Lifetime EP0804245B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
SI9530289T SI0804245T1 (en) 1994-04-27 1995-04-15 Collagen preparation for the controlled release of active substances

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DE4414755 1994-04-27
DE4414755A DE4414755C2 (de) 1994-04-27 1994-04-27 Kollagenzubereitung zur gesteuerten Abgabe von Wirkstoffen, Verfahren und Verwendung
PCT/EP1995/001428 WO1995028964A1 (fr) 1994-04-27 1995-04-15 Preparation de collagene pour la liberation controlee de principes actifs

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EP0804245A1 true EP0804245A1 (fr) 1997-11-05
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JP3865077B2 (ja) 2007-01-10
AU2307895A (en) 1995-11-16
DE4414755A1 (de) 1996-01-11
AU695621B2 (en) 1998-08-20
PL316659A1 (en) 1997-02-03
NO309256B1 (no) 2001-01-08
SK138096A3 (en) 1997-08-06
NO964539D0 (no) 1996-10-25
GR3030955T3 (en) 1999-11-30
US6761908B1 (en) 2004-07-13
EP0804245B1 (fr) 1999-05-26
FI964253L (fi) 1996-10-22
HUT75468A (en) 1997-05-28
ES2134468T3 (es) 1999-10-01
HU9602948D0 (en) 1996-12-30
DK0804245T3 (da) 1999-11-29
NO964539L (no) 1996-12-18
DE4414755C2 (de) 2000-11-16
ATE180409T1 (de) 1999-06-15
IL113326A (en) 2000-01-31
DE59506057D1 (de) 1999-07-01
NZ284476A (en) 1998-08-26
PL179952B1 (en) 2000-11-30
JPH09512257A (ja) 1997-12-09
CZ291190B6 (cs) 2003-01-15
CZ310896A3 (en) 1997-06-11
IL113326A0 (en) 1995-07-31
ZA953410B (en) 1996-04-09
MY114090A (en) 2002-08-30
WO1995028964A1 (fr) 1995-11-02
FI964253A0 (fi) 1996-10-22
SK281461B6 (sk) 2001-04-09
FI118415B (fi) 2007-11-15
KR970702733A (ko) 1997-06-10

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